Malaria: Mechanisms of Erythrocytic Infection and Pathological Correlates of Severe Disease

Haldar, Kasturi; Murphy, Sean C.; Milner, Dan; Taylor, Terrie E.

doi:10.1146/annurev.pathol.2.010506.091913

Cited by 185 publications

(177 citation statements)

References 177 publications

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“…Nevertheless, years of studies on malaria have progressively shown an important role for proinflammatory cytokines in disease pathogenesis (34,35). It is currently known that parasite sequestration is exacerbated by cytokine-mediated up-regulation of host endothelial receptors that bind to parasitized erythrocytes (i.e., intracellular adhesion molecule-1, vascular cellular adhesion molecule) (15,33,35,36). Studies in mice with deficiency in several inflammatory mediators (e.g., TNF-α) (37), other cytokines, and chemokines (38) suggest that the ECM model used in this study is mainly a cytokine-associated encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

103

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Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.immunotherapy | innate immunity | nucleic acid recognition | inflammation

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Section: Discussionmentioning

confidence: 99%

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

103

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“…Deaths attributable to CM, as defined by WHO guidelines, have been observed in the absence of parasite sequestration within the brain (Clark et al 2003 ;Taylor et al 2004 ;Haldar et al 2007). Furthermore, parasite sequestration has been observed in individuals that did not develop severe cerebral malaria (Silamut et al 1999 ;Seydel et al 2006).…”

Section: T H E R O L E O F P a R A S I T E S E Q U E S T R A T I Omentioning

confidence: 99%

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

et al. 2009

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Cerebral malaria is a life-threatening complication of malaria infection. The pathogenesis of cerebral malaria is poorly defined and progress in understanding the condition is severely hampered by the inability to study in detail, ante-mortem, the parasitological and immunological events within the brain that lead to the onset of clinical symptoms. Experimental murine models have been used to investigate the sequence of events that lead to cerebral malaria, but there is significant debate on the merits of these models and whether their study is relevant to human disease. Here we review the current understanding of the parasitological and immunological events leading to human and experimental cerebral malaria, and explain why we believe that studies with experimental models of CM are crucial to define the pathogenesis of the condition.

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“…However, one of the best predictors of whether a patient will develop severe malaria (including CM) is not the number of parasites circulating freely in the bloodstream (blood parasitemia), but instead, the total number of parasites in the whole body, including those sequestered in tissues (2,3). Postmortem studies of brains from CM patients show that sequestration of parasitized RBCs (pRBCs) within the brain microvasculature is a major histological feature of this disease (4)(5)(6). Furthermore, treatment with antiparasitic drugs, such as artesunate, kills parasites faster and reduces case fatality in patients with CM (7), compared with slower acting drugs such as quinine.…”

mentioning

confidence: 99%

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

Haque

Best

Unosson

et al. 2011

The Journal of Immunology

170

210

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Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8+ T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8+ T cells expressed granzyme B (GzmB). Furthermore, gzmB−/− mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4+ T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8+ T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8+ T cell-derived perforin and GzmB, but not IFN-γ. In wild-type mice, full activation of brain-recruited CD8+ T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8+ T cells dictates the onset of perforin/GzmB-mediated ECM.

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Malaria: Mechanisms of Erythrocytic Infection and Pathological Correlates of Severe Disease

Cited by 185 publications

References 177 publications

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

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